This Program Project emphasizes the molecular and cellular events of mammalian implantation and placental formation, an essential but little- studied process in early reproduction that has great significance for human health. The purpose of the Program is to define the role of genes that are essential for implantation and thus to achieve a basic understanding of the interactions between the embryo and uterus that establish pregnancy. The Program focuses on the peri-implantation development of the three tissue lineages that mediate implantation and develop into the placenta and fetal membranes, namely, trophoblast, extraembryonic endoderm, and extraembryonic mesoderm. Four projects examine the roles of individual membranes of several superfamilies of genes whose products are implicated in controlling peri-implantation development and implantation. These include the extracellular matrix receptors, or integrins, proteases and their inhibitors, peptide growth factors and their receptors, and HLH and other transcription factors. Project I examines the role of integrin receptors for extracellular matrix in peri-implantation development of trophoblast and primitive endoderm; Project II analyzes the roles of helix-loop-helix transcription factors in regulating human trophoblast invasion; Project III studies the mechanisms regulating growth, cell division and differentiation during morphogenesis of extraembryonic lineages and in the invasive process in vivo; and Project VI analyzes the differentiation and morphogenesis of extraembryonic mesoderm, especially the allantois. The Projects are supported by an Administrative Core, which provides fiscal management, and two research cores, the Morphology/Cytogenetics Core, which provides histological, in situ hybridization, confocal microscopy, and chromosomal analysis services, and the Cell Culture/Targeted Mutagenesis Core, which provides cell culture and genetic transformation services, including all the activities needed for targeted mutagenesis in mice. The proposed studies have major implications for human health problems, including syndromes of infertility and early pregnancy loss, inefficient implantation rates of embryos generated through medically assisted conception, and diseases of the trophoblast such as choriocarcinoma, hydatidiform mole and pre-eclampsia. These problems can ultimately be resolved only through mammalian studies, as undertaken in the Program, which examine the fundamental mechanisms of embryo-maternal interactions.